Medical powder

ABSTRACT

A safe medical powder with excellent performances which is a magnetosensitive powder for diagnosis, therapy, or drug delivery and which, even when placed in the body for a prolonged period, neither suffers a decrease in magnetic sensitivity nor releases ions, etc. The medical powder comprises a base particle of a ferromagnetic metal having thereon a coating layer, wherein at least the outside of the coating layer comprises a bioinert substance. Preferably, the coating layer comprising a bioinert substance comprises a layer comprises a hydrolysate of an alkoxide compound.

TECHNICAL FIELD

The present invention relates to a magnetic medical powder. Moreparticularly, this invention relates to a magnetic medical powder whichis used as a drug carrier for drug delivery, an immunolatex,immunobeads, a medium for hyperthermia, etc.

BACKGROUND ART

A medical powder which comprises a polymeric microsphere obtained by apolymerization method, such as emulsion polymerization, soap-freeemulsion polymerization, and having thereon an immobilized antigen orantibody, and which is used for diagnosis where its cohesiveness with anantigen or antibody as the substance to be detected is examined isconventionally known as an immunolatex. A technique of using a labeledantibody as the immobilized antibody in an immunolatex is used forheightening detectability in diagnosis. Also, a technique in which adrug is supported on an immnunolatex together with an antibody and thisimmunolatex is used for delivering the drug to, e.g., cancer cellshaving an antigen responsive to the supported antibody, is used.

Beads are more frequently used as drug carriers for drug delivery thanlatexes because they have the higher ability to support drugs. The term"beads" means polymeric microspheres having larger particle diametersthan the latexes. Latexes have particle diameters in the range of about100 Å to about submicron sizes (1 μm or less), while beads have particlediameters in the range of submicron sizes to several millimeters. Thebeads comprising a polymeric compound and having thereon an immobilizedantigen or antibody are generally called immunobeads.

Beads comprising a polymeric compound which contain a drug embeddedtherein and have thereon an immobilized antibody are used for deliveringthe drug to a diseased part where a responsive antigen is present.Namely, these are a kind of drug delivery beads.

Although biodegradable natural polymeric compounds, i.e., gelatin,starch, fibrinogen, and the like, have been used as preferred beadmaterials for such drug delivery beads, they have drawbacks, forexample, that particle diameter control is difficult, beads of constantquality are difficult to obtain, and storage is difficult. Consequently,use of synthetic or semisynthetic polymeric compounds is progressing.

The immobilization of an antigen or antibody on the latex particles orbeads is accomplished, for example, by bonding the protein (constituentsubstance of the antigen or antibody) with a condensing agent, e.g.,cyanogen bromide or carbodiimide, to a reactive group, e.g., a hydroxylgroup, an amino group, or a carboxyl group, present on the main chain ofthe polymeric compound constituting the latex particles or beads or tosuch a reactive group incorporated as a side chain into the constituentpolymeric compound through substitution.

Another known example of the fields where the immunobeads are utilizedis the field of cell separation. An example of immunobead utilization inthe field of cell separation is in therapy or diagnosis. In thisapplication, magnetic immunobeads (hereinafter referred to also as"magnetosensitive immunobeads") are prepared by fixing a ferromagneticsubstance to polymeric beads, for example, by incorporating an ironpowder or another ferromagnetic material powder into the beads orembedding aggregates of ferromagnetic material powder particles in thebeads and further immobilizing an antibody to the surface of the beads.The magnetosensitive immunobeads are introduced into the blood to allowthe immunobeads to react with a responsive antigen (pathogenic antigen)present in the blood to thereby immobilize the antigen to theimmunobeads. The magnetosensitive immunobeads are then collected with amagnet to thereby remove the antigen from the blood. Themagnetosensitive immunobeads thus used for removing a pathogenic antigenfrom the blood are used also for removing tumor cells from bone marrow.

Still another use of magnetosensitive beads is in drug delivery.Specifically, magnetosensitive beads are used as a therapeutic powder ina drug delivery system in which the magnetosensitive beads areintravenously injected into a living body, e.g., human body, and amagnet or the like is externally applied to a diseased part to lead thedrug-supporting magnetosensitive beads to the diseased part by means ofmagnetic induction. An example of these magnetosensitive beads is amedical powder comprising a polymeric microsphere which contains amagnetite as a base material embedded therein and simultaneously have adrug supported thereon.

Furthermore, a medical powder comprising a metallic conductor is used asa heating medium in the method of treatment called hyperthermia, inwhich a powder of a conductor such as a metal (a metal powder isgenerally used) is introduced into a part affected by terminal cancerand the affected part is burnt by high-frequency induction heating.

The current medical powder which comprise a polymeric microspherecontaining a magnetite as a base material embedded therein and is usedfor the diagnostic-therapeutic system described above (i.e., one form ofthe magnetosensitive beads described above) employs a magnetite as abase material. However, since the magnetic force applied with currentmagnetic inductors is insufficient for these current medical powders,the locations of diseased parts to which the medical powders can be ledare limited. There is hence a desire for a medical powder (i.e.,magnetosensitive beads) having higher magnetic sensitivity.

Additionally, during long-term residence in a living body, the currentmagnetosensitive beads suffer changes such as, e.g., oxidation of theembedded base material and come to have reduced magnetic sensitivity.There have also been cases where ions such as iron ions are releasedfrom current magnetosensitive beads. Thus, the current magnetosensitivebeads have the unsolved problems described above.

An object of the present invention is to eliminate the problems of thecurrent magnetosensitive beads and to provide a safer medical powderwhich has excellent performances when used for the diagnosis, therapy,or drug delivery described above.

DISCLOSURE OF THE INVENTION

As a result of intensive studies, the above object has been found to beaccomplished by the following medical powder of the present invention:

(1) A medical powder comprising a base particle of a ferromagnetic metalhaving thereon a coating layer, wherein at least the outside of thecoating layer comprises a bioinert substance; and

(2) The medical powder according to the above (1) wherein the coatinglayer comprising a bioinert substance contains a layer comprises ahydrolysate of an alkoxide compound.

The base particles of a ferromagnetic metal used in the medical powder,i.e., magnetosensitive beads, of the present invention are made of aferromagnetic material preferably having a magnetization of 120 emu/g ormore in a magnetic field of 10 kOe (kilo-oersted).

Examples of the ferromagnetic metal include pure iron, nickel metal,silicon steel, iron-nickel alloys, iron-cobalt alloys, iron-aluminumalloys, and iron-cobalt-nickel alloys, from the standpoints of highsaturation magnetization, high magnetic permeability, and small coerciveforce. The iron and nickel are preferably ones obtained from thecarbonyl compounds of iron and nickel, respectively. In particular, theiron obtained from carbonyl iron is more preferred from the standpointsof purity and profitability. Also, electrolytic iron and reduced ironcan be used.

When a metal or alloy, such as the pure iron, nickel metal, or aniron-aluminum alloy, is exposed as it is to an aqueous solutioncontaining an electrolyte such as unmodified blood plasma, it changesand comes to have a reduced magnetization and reduced magneticpermeability and to ionize and release ions. Accordingly, the surface ofthe base material in the present invention is coated with a bioinertsubstance in order to protect such changes of the base material.

The term "bioinert substance" herein means a substance which, even ifexposed over long to an aqueous electrolyte solution, such as blood oranother living-body tissue fluid, is not adversely influenced by theelectrolyte solution to cause ion release, etc., and which, even ifincorporated into a living body, does not exert any harmfulphysiological action.

Examples of the bioinert substance include organic polymers, forexample, olefin oligomers (e.g., polystyrene, polypropylene,polybutene), vinyl oligomers (e.g., polyacrylic acid, polymethacrylicacid), diene oligomers (e.g., polybutadiene, polypentadiene,polychloroprene), and copolymers thereof; and metal oxides. Examples ofthe metal oxides include oxides of iron, nickel, chromium, titanium,aluminum, and silicon. A suitable kind of metal oxide is selectedaccording to the property to be imparted to the surface of the powder.Although the thickness of each layer of the metal oxide film is notparticularly limited, it is preferably in the range of 0.01 to 20 μm.

Organic polymers are advantageous in supporting a drug or an antigen orantibody thereon; on the other hand, metal oxides are advantageous inthat they can effectively prevent a body fluid from penetratingtherethrough and reaching the metallic base material.

Examples of methods for coating the surface of a base material with ametal oxide include methods of solid deposition in a liquid phase, suchas electroplating and electroless plating, and methods of film formationin a gas phase, such as plasma-assisted CVD and plasma-assisted PVD.These methods can form a corrosion-resistant inorganic coating. Otherexamples include the method called a sol-gel method, in which a metalalkoxide is hydrolyzed in a solution. Since this sol-gel method canyield a coating layer which has an even thickness and is dense, it issuitable for use in the surface coating of a base powder for the purposeof preventing the base material from being changed by an aqueoussolution containing an electrolyte, such as blood or another body fluid,as in the case of the base material in the present invention.

The sol-gel method based on the hydrolysis of a metal alkoxide is aprocess for powder coating with a metal oxide which comprises dispersingbase particles into a solution of an alkoxide of the same metal as thatof the metal oxide film to be deposited on the base particle surface,and hydrolyzing the metal alkoxide to thereby generate a sol of an oxideof the metal on the surface of the base particles. The sol generateddeposits on the surface of the base particles and turns into a gel.Thus, a film of the metal oxide gel generates evenly on the baseparticles.

This method for powder coating with a metal oxide may be repeated tocoat the base particles with layers of the same or different metaloxides, whereby a powder coated with a multilayered metal oxide film canbe produced.

On the other hand, methods for coating the surface of base particleswith an organic polymer film include the following methods besides thegas-phase surface polymerization of a base material and plasma-assistedCVD:

(1) a method in which base particles are emulsified or suspended inwater together with a polymerizable monomer and emulsion polymerizationor suspension polymerization is conducted respectively using an emulsionpolymerization catalyst or a water-soluble polymerization catalyst,e.g., a catalyst such as ammonium persulfate, to obtain anorganic-polymer coated powder as an emulsion polymerization orsuspension polymerization product containing the base particles;

(2) a method in which the above-described emulsion polymerization orsuspension polymerization product containing base particles is subjectedas a base to seed polymerization to obtain an organic-polymer coatedpowder; and

(3) other methods, for example, in which an organic-polymer coatedpowder is obtained by in situ polymerization.

Examples of the monomer for use in polymerization methods for coatingthe surface of base particles with an organic polymer film, e.g., in theemulsion polymerization, suspension polymerization, and seedpolymerization described above, include the vinyl monomers and olefinmonomers shown below. However, the monomers are not particularly limitedthereto, and other monomers including oligomers and compounds modifiedwith a polymerizable monomer are also usable.

Examples of ordinarily used polymerizable monomers includearyl-substituted vinyl monomers (for example, styrene, methylstyrene),unsaturated hydrocarbon monomers (for example, ethylene, propylene,butadiene, isoprene), and acrylic monomers (e.g., for example,acrylonitrile, (meth)acrylic esters, (meth)acrylamide, (meth)acrylicacid), vinyl acetate, maleic anhydride, and N-vinylpyrrolidone.

Organic polymers are preferred to metal oxides and the like as thematerial of the outermost layer of the medical powder to be injectedinto a living body, from the standpoint that organic polymers are moreadvantageous for supporting a drug or an antigen or antibody thereon.Consequently, a preferred embodiment of the medical powder of thepresent invention comprises a ferromagnetic material as a base material,a metal oxide film formed thereon which has a dense structureimpermeable to water, ions, etc., and an organic polymer coating filmformed on the outer side of the metal oxide film.

For example, the sol-gel method described above is used to deposit asilicon oxide film from a silicon alkoxide solution on a base made ofpure iron, and a hydroxypropyl cellulose film is adsorbed thereonto as asubstance-supporting film. The resultant particles are used as seeds toconduct seed polymerization in a monomer system comprising acrylic acidand styrene. Thus, medical beads each having a shell mainly comprisingpolystyrene can be produced.

After an antibody is immobilized on the polystyrene shells of the beadsthus designed, the beads can be utilized as immunobeads for cellseparation, etc.

If the magnetosensitive beads described above are used for drugdelivery, a wide variety of drugs can be embedded in the polymericbeads, including carcinostatic agents, steroid agents, antibiotics,local anesthetics, and radioisotopes for radiation therapy. From thestandpoint of facilitating the release of such an embedded drug in adiseased part, it is, for example, preferred to form the shellscomprising an organic polymeric substance so as to have a multilayeredstructure or a composite phase and to fix a drug to the polymer part. Itis also possible to apply an alternating magnetic field to acceleratedrug release.

With respect to heating media for use in the above-described method oftreatment called hyperthermia, in which a diseased part is burnt fortreatment by high-frequency induction heating, no media havingmagnetosensitivity have been used so far. In this method of treatment,the introduction of the metallic conductor into a diseased part has beenconducted through surgical incision or local injection, which isaccompanied with much pain. However, by imparting magnetic sensitivityto a heating medium for hyperthermia, the heating medium can beintroduced into the blood by intravenous injection, and the magneticmetallic conductor can be inducted to a diseased part by means of themagnetic induction caused by a magnetic field externally applied to thediseased part. Thus, the heating medium for hyperthermia can beintroduced into the diseased part exceedingly easily. There is anotheradvantage that by keeping a magnetic field being externally applied tothe diseased part after the introduction, the heating medium can beprevented from diffusing from the diseased part with the lapse of time.

BEST MODES FOR CARRYING OUT THE INVENTION

The present invention will be explained in more detail by reference toExamples, but the invention should not be construed as being limited bythe following Examples.

Production of Medical Powder

EXAMPLE 1

First Layer, Silica Coating

Into 100 ml of ethanol was dispersed 10 g of a powder of pure iron(carbonyl iron powder manufactured by BASF; average particle diameter,1.8 μm; 201 emu/g at 10 kOe). The container was heated with an oil bathto keep the temperature of the liquid at 55° C. To this dispersion wereadded 6 g of silicon ethoxide, 6 g of 29% ammonia water, and 8 g ofwater. This mixture was allowed to react for 2 hours under stirring.

After the reaction, the reaction mixture was diluted and washed withethanol and filtered. The solid matter was dried in a vacuum dryer at110° C. for 3 hours. After the drying, the resultant powder was heatedwith a rotary tubular oven at 650° C. for 30 minutes to obtain silicacoated powder A₁. The film thickness of the silica coated powder A₁obtained was 75 nm. The powder was excellent in dispersed state.

Second Layer, Titania Coating

After the heating, 10 g of the silica coated powder A₁ obtained wasredispersed into 200 ml of ethanol. The container was heated with an oilbath to keep the temperature of the liquid at 55° C. To this dispersionwas added 5 g of titanium ethoxide. This mixture was stirred. A solutionprepared by mixing 30 ml of ethanol with 8.0 g of water was addeddropwise to the above mixture over 60 minutes, and the resultant mixturewas allowed to react for 2 hours. The particles were then vacuum-driedand heated to obtain titania-silica coated powder A₂. The titania-silicacoated powder A₂ obtained was good dispersiblity, and was an independentparticle. The titania film of this titania-silica coated powder A₂ had athickness of 50 nm.

Third Layer, Polystyrene Coating

To 600 g of distilled water was added 500 g of styrene monomer. Whilethis mixture was heated to 70°C. under stirring, sodium lauryl sulfatewas added thereto to emulsify the monomer. This emulsion was mixed with25 g of the titania-silica coated powder A₂ whose surface had beenlipophilized with methacrylic acid, and the resultant mixture wasagitated at a high speed to sufficiently mix the ingredients. An aqueousammonium persulfate solution was added thereto in an amount of 10% toinitiate a polymerization reaction. The mixture was allowed to react for4 hours under stirring. After completion of the reaction, the reactionmixture was diluted with 2 liters of distilled water, and thesupernatant was discarded by decantation to collect the precipitate.

The precipitate was dried on a filter paper to obtainpolystyrene-titania powder A. In a magnetic field of 10 kOe, the powderA obtained had a magnetization of 148 emu/g, which was about 1.5 timesthe magnetization of magnetite (90 emu/g) which had conventionally beenused.

In Vivo Stability of Powder

EXAMPLE 2

In 500 ml of physiological saline held at 38° C. with an oil bath wasimmersed 10 g of the polystyrene-titania powder A for 24 hours.

As a result, the powder A underwent no change in appearance and no ironions were detected in the physiological saline. Furthermore, themagnetization of the powder A in a magnetic field of 10 kOe after theimmersion in physiological saline was 146 emu/g, which was almost thesame as the magnetization value of 148 emu/g before the immersion.

COMPARATIVE EXAMPLE 1

On the other hand, 10 g of a powder B obtained by subjecting a powder ofpure iron (carbonyl iron powder manufactured by BASF; average particlediameter, 1.8 μm; 201 emu/g at 10 kOe) to only the polystyrene coatingdescribed in Example 1 was immersed for 24 hours in 500 ml ofphysiological saline held at 38° C. with an oil bath in the same manner.

As a result, hydrogen generation was observed at 17 minutes afterinitiation of the immersion of the powder B. After 4 hours, a dark-brownpowder and a black powder were observed. After 24 hours, the surface ofthe powder B had been completely oxidized and turned dark-brown, and thephysiological saline had an iron ion concentration of 1.5%. Themagnetization of the powder B in a magnetic field of 10 kOe, which hadbeen 166 emu/g before the immersion in physiological saline, was 25emu/g after the immersion. Namely, the magnetization thereof decreasedto about 85% of the original value.

INDUSTRIAL APPLICABILITY

According to the present invention, a safe medical powder havingexcellent performances can be provided which, even if placed in the bodyfor a prolonged period of time, neither suffers a decrease in magneticsensitivity nor releases ions, etc.

Due to the medical powder provided by the present invention, not onlymagnetosensitive immunobeads having excellent performances can beprovided to thereby greatly contribute to the field of cell separation,e.g., the separation of harmful cells from bone marrow, but also anexcellent magnetically inducible drug can be provided to thereby greatlycontribute to therapeutic fields, e.g., the field of drug deliverysystems.

Furthermore, since the medical powder of the present invention can beeasily produced, it can be supplied at low cost. The powder can bestored stably over long and can be supplied stably. Therefore, thepresent invention is highly effective also from the standpoint ofprofitability.

What is claimed is:
 1. A medical powder comprising a base particle of aferromagnetic metal having thereon at least one metal oxide layer, andan outside coating layer comprising bioinert substance, selected fromthe group consisting of polystyrene, polypropylene, polybutene,polyacrylic acid, polymethacrylic acid, polybutadiene polypentadiene,polychloroprene, and copolymers thereof, and a drug or medicalcomponent.
 2. The medical powder according to claim 1, wherein the atleast one metal oxide layer comprises a hydrolysate of an alkoxidecompound.
 3. The medical powder according to claim 1, wherein the metaloxide is selected from oxides of iron, nickel, chromium, titanium,aluminum and silicon.
 4. The medical powder according to claim 1,wherein the drug or medical component is selected from the groupconsisting of an antigen, an antibody, a carcinostatic agent, a steroidagent, an antibiotic, a local anesthetic and a radioisotope forradiation therapy.
 5. The medical powder according to claim 1, whereinthe drug or medical component is releasable from the powder.